The long-term goal of this research is to understand how LSA-1 may contribute to a vaccine to prevent morbidity from human P. falciparum infection. Several lines of evidence indicate that LSA-1 is a logical vaccine candidate molecule. Firstly, HLA-Bw53-linked protection against morbidity in West Africans is associated with CTL responses specified by a nonapeptide encoded in the C-terminus of LSA-1 (28,29). Secondly, our preliminary results -indicate that synthetic peptides encoding 3 putative T cell epitopes in LSA-1 drive proliferative responses and IFN-gamma and/or IL-4 production by peripheral blood mononuclear cells from North Americans immunized with irradiated sporozoites and adult African residents of P. falciparum endemic areas. The relationship between LSA-1 specific immunity and morbidity in endemic areas, has, however not been ascertained. The current proposal will address this gap in knowledge in the Wosera area of Papua New Guinea, where the AID Malaria Vaccine Epidemiology and Evaluation Program has ongoing studies. The specific aims are: 1. To define the dominant antibody isotype and T cell responses to LSA-1 in adults who have demonstrated resistance to the morbid complications of P. falciparum infection. We will determine whether CD4 Th1 or Th2 responses are preferentially recalled and determine whether CD8+ T cells produce IFN-gamma in response to LSA-1. The latter will be linked with class I HLA phenotypes, which are known for the subjects. 2. To evaluate in a prospective cohort study the relationship between malaria morbidity and immune reactivity to LSA-1 in 2-9 year old children. 3. To examine LSA-1 genetic polymorphisms, particularly in the C-terminus where 2 T cell and CTL epitopes exist. These studies will advance knowledge of the mechanisms by which LSA-1 may contribute to a human P. falciparum vaccine.